Genetic studies have shown greatly increased incidence of emphysema in individuals homozygous for alpha1-antitrypsin (AAT) deficiency. The relationship between heterozygosis and increased incidence of emphysema in humans has not been clearly demonstrated. Overlap of AAT levels between normals and heterozygotes, diversities of environmental and occupational histories, age and sex differences make human epidemiological studies difficult to execute. The proposed experimental approach utlitizes an animal model consisting of inbred mouse strains possessing high AAT and low AAT serum levels, and F1 hybrids of these strains exhibiting intermediate AAT levels. These mice will be exposed to low concentrations of nitrogen dioxide for extended periods of time (up to 18 months) and the correlation between progression of lung pathology and AAT level will be determined. Differences in susceptibility of these mouse strains to bacterial pneumonia and influenza virus infection at various time intervals of exposure to nitrogen dioxide will also be correlated with their AAT levels. Investigations will be carried out to determine how sex and age factors affect the AAT levels of these mouse strains and hybrids and to document progression of lung pathology in them after exposures to respiratoy challenge.